In the world of controlled release drug delivery systems there have been certain axioms upon which much development has been based. One such axiom is that ‘flatter is better’ i.e. the flatter the delivery curve is vs. time the better the system will behave. It is therefore considered desirable to have delivery systems that give essentially a zero order release profile. In drug delivery systems having a zero order release profile, the amount of drug released is not dependent on the amount left within the delivery system and remains constant over the entire delivery profile.
Tailoring the drug delivery to the needs of the therapy is another axiom of delivery improvement. One can conceive of therapies that need a sudden burst of drug after several hours of constant delivery or a change in the rate of drug delivery after several hours. A swelling hydrogel tablet delivery system or an eroding tablet delivery system, gives drug delivery that tapers off with time. In the eroding system, the surface that provides drug delivery is shrinking with time so the rate falls off proportionally. If the drug is delivered by diffusion through a non eroding hydrogel the rate falls off as drug depletion changes the force of the chemical gradient. These systems do not offer the opportunity to carefully tailor the drug release rates.
Zero order delivery has been achieved with the “Oros” osmotic pumps as is documented in many patents held by the Alza company (e.g. U.S. Pat. No. 3,995,631 to Higuchi, T. et. al., and U.S. Pat. No. 3,977,404 to Theeuwes, F.). The “Oros” system is based on osmotic pressure pushing the drug out of an almost microscopic orifice. The zero order profile is achieved due to the constant, small, cross section of the orifice being the rate determining step in the drug release. The “Oros” system has proven itself in several products but it has limitations. It is most useful for soluble drugs, with insoluble drugs having limited applicability. The technology of manufacture is somewhat complicated with the need of a laser drilled hole in the semipermeable coating. The drug release through an almost microscopic hole can also lead to several drawbacks. Clogging of the hole may limit drug release and the streaming of a concentrated solution of drug from the delivery system to the intestinal lumen can cause damage to the intestinal wall (see Laidler, P.; Maslin, S. C.; and Gihome, R. W. Pathol Res Pract 1985 180 (1) 74–76). Delays of the start of drug release can be achieved by coating the system (such as with an enteric coating) but the small orifice may be clogged by the coating and give erratic results in opening (if at all). The “Oros” system is best suited for a simple zero order delivery profile. Complicated patterns can be achieved with the “Oros” such as described in U.S. Pat. No. 5,156,850 to Wong, P. S. et. al. and in PCT WO 9823263 to Hamel, L. G. et. al., with concomitant complication of the manufacture and of the system, and without solving the drawbacks of the almost microscopic hole.
Zero order delivery profiles have been achieved with clever manipulation of the geometric surface of drug delivery as embodied in the “Geomatrix” delivery systems. (U.S. Pat. No. 4,839,177 to Colombo, P. et. al. and U.S. Pat. No. 5,422,123 to Conte, U. et. al.). These systems achieve a zero order profile by sandwiching the drug delivery layer between two layers that are impermeable. Only the drug delivery layer is eroded and the cross-section of the eroding layer is constant. Again here, there are several drawbacks. The manufacture of the system requires special equipment to produce two and three layer tablets. The system does not easily lend itself to changing the rate of delivery during the release profile. The amount of drug available in the tablet is somewhat limited since only one of the layers is used for drug delivery. The zero order profile may not be followed up to 100% of drug release due to tablet breakup once most of the central layer has eroded.
There is, therefore, still room for an improved zero order drug delivery system that is easy to manufacture, easy to control and allows one to make changes in the rate of drug delivery at a predetermined time in the release profile.